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  • Tuberculosis

    Jed Gorden MDUniversity of Washington

    Vietnam Lecture Series 2001

  • Tuberculosis

    Mycobacterium Tuberculosis (TB) = #1 Cause of Death Worldwide from a Single Infectious Agent

    1993 World Health Organization: Declared TB Global Health Emergency

  • TB: History

    Earliest Archeological Evidence of Spinal TB is from Egyptian Mummies, 4000 BCE.

    Earliest Evidence of Pulmonary TB 1000 BCE in a 5 Year old Boy

  • TB: History

    Earliest Written Description 668-626 BCE:

    The Patient Coughs Frequently, His sputum is Thick and Sometimes Contains Blood. His Breathing is Like a Flute, His Skin is Cold but His Feet are Hot. He Sweats Greatly

    and his Heart is Much Disturbed.

  • TB: Ancient Names

    Hindus = Sosha = CoughRayakshma = Waisting

    Greeks = Phtisis = To Waste

    English Term From Latin = Consumption

  • TB: History

    TB Peak = Industrial Revolution 17th- 18th CenturyResulting in 25-30% of all Adult Deaths in Europe

  • TB: Epidemiology

    Estimates for 1990 World Wide # Infected = 1.7 Billion World Wide # Deaths = 3 Million SE Asia # Infected = 426 Million SE Asia # New Cases = 2.47 Million SE Asia # Deaths = 900 Thousand

  • TB: Transmition

    Infection = Person to Person via Airborne Infectious Aerosol:


  • Transmission and Pathogenesis

  • TB: Transmition

    Aerosolized Droplets 5 Micrometers = 1-400 Bacilli

    Estimated 5-200 Organisms Required for Infection

  • TB: Transmition

    Influences on Becoming Infected:Infected Contact

    Duration of Exposure*Ventilation in Infected Environment

    *Suspended Airborne Particles are Infectious after Source Leaves the Room

  • TB: Natural History

    Inhaled Particle*


    Immune System Activation*

    Granuloma Formation

  • CXR with evidence of TB infection

  • TB: Disease

    Estimated Only 10% of Immunocompitent People Infected With TB (PPD+) Will Develop Clinically Significant Disease

    50% in First 2-3 years Following Exposure 50% in Remote Future

  • TB: Disease

    Estimated Only 10% of Immunocompitent People Infected With TB (PPD+) Will Develop Clinically Significant Disease

    50% in First 2-3 years Following Exposure 50% in Remote Future

  • TB: Determinants of Disease Defects in Cell Mediated Immunity

    Advanced AgeMalnutrition

    Genetic FactorsImmunosuppressive Meds

    Co-existing Disease: DiabetesMalignancyHIVRenal Failure

  • TB: Disease Pattern

    Primary Tuberculosis

    Reactivation Tuberculosis

  • TB: Primary

    Associated With New TB Exposure Symptoms in Series of 517 New Converters:

    Fever 70% (Duration 2-10 Weeks)Chest Pain 25%

    Pleuritic Chest PainErethema Nodusum Lower Extremities

    (Women > Men)

  • TB: Primary Chest X-Ray

    Hilar Adenopathy 64% (Children > Adults) Hilar Changes Right > Left Pleural Effusion 29% (Adults > Children) Unilateral Infiltrate/Ipsolateral Hilar Nodes 27%

  • Possible primary tuberculous pneumonia

  • TB: Reactivation

    Accounts For 90% of Adult non HIV TB

    Reactivation = Result of a Previously Dormant Organism Implanted Years Before by a Primary Infection

    Most Common Location = Apical Post Segment of Lung

  • TB Reactivation: Symptoms

    Nonspecific Cough 78%

    Weight Loss 74% Fatigue 68%

    Temperature 60% Night Sweats 55% Hemoptosis 37%

  • TB Reactivation: Physical Exam

    Non Specific

  • Apical Cavitary Disease

  • TB: Diagnosis

    PPD Sputum Examination

    Chest X-Ray Culture

  • TB: PPD

    PPD = Purified Protein Derivative

    The Tuberculin Skin Test Identifies Individuals Who Have Been Infected With Mycobacterium Tuberculosis, it Does not Differentiate Between Old and New Infection

  • TB: PPD

    Dose of Tuberculin = 5TU

    Injection Site = Intradermally Dorsal Side of Forearm

    Inflammatory Reaction = 24-72 Hours

    Result Test in 48-72 Hours (If Positive at 6 Days = true Positive)

  • Testing for TB Disease and Infection

  • TB: PPD Resulting

    Diameter of Induration = Determinant of Disease

    Technique: Use Ball Point Pen Start 1-2 cm Away from Margin of Test When Ball Point Pen Reaches the Margin Resistance is Felt. Repeat From Opposite Side. Distance between Lines = Diameter

  • Reading the Tuberculin Skin Test

    Read reaction 48-72 hours after injection

    Measure only induration

    Record reaction in millimeters Correct Measurement

  • PPD Guidelines for Interpretation Size of Induration

    < 5mm

    > 5mm

    > 10mm

    > 15mm

    Considered Positive

    Never = +

    HIV+Close Contact of TB+

    + Chest X-Ray

    IV Drugs/HIV-At Risk Disease

    High Risk GeographyAll Patients

  • TB Chemo prophylaxis

    Isoniazide Prophylaxis Given to Tuberculin Reactors Reduces the Risk of Active TB by 90%

  • TB Chemo prophylaxis

    Isoniazid 300mg Single Daily Dose 6-12 Months

    HIV+ Patients Isoniazid 300mg Daily 12 Months

    Alternative: Isoniazid 15 mg/kg Twice Weekly 6-12 Months

    *All Regiments Require Patient Compliance For Efficacy

  • Risk of Isoniazid

    Hepatitis = Major Toxic Effect of Isoniazid< 20 Years Old = 0% Risk

    20-34 Years Old = 0.3% Risk35-49Years Old = 1.2% Risk50-65 Years Old 2.3% Risk

    Risk Increased With Alcohol Consumption

  • Risk of Isoniazid

    Peripheral Neuropathy

    Highest Risk in Diabetes, Malnutrition, Alcoholism

    Peripheral Neuropathy Prevention Co-Administer Pyridoxine

  • Micobacterium Tuberculosis in Sputum

  • Principles of Tuberculosis Treatment

    Regimens Must Contain Multiple Drugs

    Drugs Must be Taken Regularly

    Treatment Must be Continued for Sufficient Time(Minimal Acceptable Duration of Treatment = 6 Months)

  • Principles of Tuberculosis Treatment

    Any Regimen is Irrelevant if Drugs Do Not Enter The Patients Body. Promoting and

    Monitoring Adherence to The Drug Regimen Are Essential For Treatment To be


  • Principles of Tuberculosis Treatment

    The World health Organization Advocates Directly Observed Therapy


  • Drugs in Current Use

    Isoniazid Rifampin

    Pyrazinamide Ethambutol


  • TB: Treatment Option 1Drug Dose (Max) Duration

    Isoniazid 5-10mg/kg/day (300mg) 6 Months

    Rifampin 10mg/kg/day (600mg) 6 Months

    Pyrazinamide 25mg/kg/day (2.5g) First 2 Months

    Ethambutol 25mg/kg/day First 2 Months

  • TB: Treatment Option 2Daily: Isoniazid+Rifampin+Pyrazinamide+EthambutolDuration: Week 1+2

    +2 Times/Week: Isoniazid+Rifampin+Pyrazinamide+

    EthhambutolDuration: Week 2-8

    +2 Times/Week: Isoniazid+RifampinDuration: Week 8-24*Total Duration of Therapy 24 Weeks*Direct Observed Therapy Required For Short Course

  • TB: Treatment Option 33 Times/Week For Total 6 Months:




    Ethambutol*Directly Observed Therapy Required Short Course

  • Adjusted Treatment Dose

    50mg/kg Max 2.5g50mg/kg Max 2.5gEthambutol

    50-70mg/kg Max 4g50-70mg/kg Max 4gPyrazinamide

    10mg/kg Max 600mg10mg/kg Max 600mgRifampin

    15mg/kg Max 900mg15mg/kg Max 900mgIsoniazid


  • Ethambutol Caution

    Ethambutol Should not Be Used if Unable to Monitor Visual Acuity, Including in Small Children

    Substitute with StreptomycinDaily Dose = 15mg/kg Max 1g/dose2x/Week Dose = 25-30mg/kg Max 1.5 g/dose3x/Week Dose = 25-30mg/kg Max 1.5 g/dose

  • Toxicities of TB Treatment

    All therapies have significant toxicity All drugs are associated with hepatitis and

    hypersensitivity reactions Unique toxicities

    INH: hepatic necrosis, peripheral neuropathy Rifampin: altered drug metabolism Pyrazinamide: hyperuricemia Ethambutol: optic neuritis Streptomycin: vestibular toxicity

  • Evaluation Response To Treatment

    Response To Anti TB Chemotherapy is Best Evaluated Through Sputum Examination

    Recommend Sputum Evaluation Every Month

    After 2 Months of Therapy 85% of Patients = Sputum negative

  • Treatment Failure

    Consider Drug Resistance To Medical regimen

    Consider Poor Patient Compliance With Medical Regimen

  • TB and HIV

    Complex synergy between HIV and TB Annual risk of progression to disease is 10%

    this is up to 100-fold higher than in HIV -

    TB is aggressive in HIV, more likely to disseminate

    TB may be AIDS-defining illness Treatment is the same, but often a longer course Interactions between HIV meds and anti-TB drugs

  • TB: BCG Vaccination

    Live Attenuated Vaccine Derived From M. Bovis

    WHO: Recommended For Young Children

    Vaccination = 60-80% Decrease in Disease Does Not Prevent Infection

    Effect of BCG on PPD Decreases With Time

  • Allocation of TB Resources

    Infection Case Finding and Treatment

    Contact Investigation and Treatment

  • TB: Summary

    Endemic Disease With Significant Mortality and Morbidity

    Resource Focus: Case Finding + Contact Treatment

    Treatment Requires Medication + Compliance

  • CASE: I A 56 Year Old Previously Healthy Woman

    Presents for Ca